The design and synthesis of a new class of RTK/HDAC dual-targeted inhibitors

Area of Science:

• Medicinal Chemistry
• Cancer Pharmacology
• Drug Discovery

Background:

• Targeted therapies, such as receptor tyrosine kinase (RTK) inhibitors, are crucial in cancer chemotherapy.
• Challenges remain, including poor response rates and acquired drug resistance to existing RTK inhibitors.
• Dual-targeting strategies offer potential to overcome these limitations.

Purpose of the Study:

• To design and synthesize novel quinazoline derivatives as dual inhibitors of histone deacetylases (HDAC) and RTKs.
• To investigate the structure-activity relationship (SAR) of these dual-targeted compounds.
• To identify specific structural features that enhance inhibitory activity against HDAC, EGFR, and HER2.

Main Methods:

• Synthesis of a new class of quinazoline derivatives.
• In vitro evaluation of inhibitory activity against HDAC, EGFR, and HER2.
• Structure-activity relationship (SAR) analysis to correlate chemical structure with biological activity.

Main Results:

• Several dual-targeted inhibitors with a quinazoline core were successfully synthesized.
• The SAR study revealed that introducing a polar hydroxamate group at the 4-position of the quinazoline core favors potent dual inhibition of HDAC and HER2.
• Compounds with this feature were more effective as HDACi/HER2i hybrids compared to HDACi/EGFRi molecules.

Conclusions:

• Novel quinazoline derivatives demonstrate potential as dual HDAC and RTK inhibitors for cancer therapy.
• The 4-position of the quinazoline core is a critical site for modulating dual inhibitory activity.
• Hydroxamate-containing compounds show promise as potent HDACi/HER2i agents, suggesting a viable strategy for overcoming drug resistance.